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Progress in Molecular Biology and... 2024Female cancers, which include breast and gynaecological cancers, represent a significant global health burden for women. Despite advancements in research pertinent to... (Review)
Review
Female cancers, which include breast and gynaecological cancers, represent a significant global health burden for women. Despite advancements in research pertinent to unearthing crucial pathological characteristics of these cancers, challenges persist in discovering potential therapeutic strategies. This is further exacerbated by economic burdens associated with de novo drug discovery and clinical intricacies such as development of drug resistance and metastasis. Drug repurposing, an innovative approach leveraging existing FDA-approved drugs for new indications, presents a promising avenue to expedite therapeutic development. Computational techniques, including virtual screening and analysis of drug-target-disease relationships, enable the identification of potential candidate drugs. Integration of diverse data types, such as omics and clinical information, enhances the precision and efficacy of drug repurposing strategies. Experimental approaches, including high-throughput screening assays, in vitro, and in vivo models, complement computational methods, facilitating the validation of repurposed drugs. This review highlights various target mining strategies based on analysis of differential gene expression, weighted gene co-expression, protein-protein interaction network, and host-pathogen interaction, among others. To unearth drug candidates, the technicalities of leveraging information from databases such as DrugBank, STITCH, LINCS, and ChEMBL, among others are discussed. Further in silico validation techniques encompassing molecular docking, pharmacophore modelling, molecular dynamic simulations, and ADMET analysis are elaborated. Overall, this review delves into the exploration of individual case studies to offer a wide perspective of the ever-evolving field of drug repurposing, emphasizing the multifaceted approaches and methodologies employed for the same to confront female cancers.
Topics: Drug Repositioning; Humans; Female; Antineoplastic Agents; Neoplasms
PubMed: 38942544
DOI: 10.1016/bs.pmbts.2024.05.002 -
Progress in Molecular Biology and... 2024In the dynamic landscape of cancer therapeutics, the innovative strategy of drug repurposing emerges as a transformative paradigm, heralding a new era in the fight... (Review)
Review
In the dynamic landscape of cancer therapeutics, the innovative strategy of drug repurposing emerges as a transformative paradigm, heralding a new era in the fight against malignancies. This book chapter aims to embark on the comprehension of the strategic deployment of approved drugs for repurposing and the meticulous journey of drug repurposing from earlier times to the current era. Moreover, the chapter underscores the multifaceted and complex nature of cancer biology, and the evolving field of cancer drug therapeutics while emphasizing the mandate of drug repurposing to advance cancer therapeutics. Importantly, the narrative explores the latest tools, technologies, and cutting-edge methodologies including high-throughput screening, omics technologies, and artificial intelligence-driven approaches, for shaping and accelerating the pace of drug repurposing to uncover novel cancer therapeutic avenues. The chapter critically assesses the breakthroughs, expanding the repertoire of repurposing drug candidates in cancer, and their major categories. Another focal point of this book chapter is that it addresses the emergence of combination therapies involving repurposed drugs, reflecting a shift towards personalized and synergistic treatment approaches. The expert analysis delves into the intricacies of combinatorial regimens, elucidating their potential to target heterogeneous cancer populations and overcome resistance mechanisms, thereby enhancing treatment efficacy. Therefore, this chapter provides in-depth insights into the potential of repurposing towards bringing the much-needed big leap in the field of cancer therapeutics.
Topics: Drug Repositioning; Humans; Neoplasms; Antineoplastic Agents; Animals
PubMed: 38942535
DOI: 10.1016/bs.pmbts.2024.03.032 -
Moving the needle on proteasome inhibitor-induced pulmonary arterial hypertension: a definite maybe.The European Respiratory Journal Jun 2024
Topics: Humans; Proteasome Inhibitors; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Bortezomib
PubMed: 38942441
DOI: 10.1183/13993003.00946-2024 -
Medicine Jun 2024Evidence on real-world clinical and economic outcomes in patients with multiple myeloma (MM) and renal impairment (RI) is limited in the United States. This... (Observational Study)
Observational Study
Evidence on real-world clinical and economic outcomes in patients with multiple myeloma (MM) and renal impairment (RI) is limited in the United States. This retrospective study aimed to generate an updated comprehensive assessment of the clinical and economic outcomes of MM patients with RI using the Medicare research identifiable files data with Part D linkage, which might assist in assessing the total clinical and socioeconomic burden of these high-risk and challenging-to-treat patients. Treatment patterns and clinical and economic outcomes in first line (1L) to fourth line (4L) therapy were described in Medicare beneficiaries (2012 to 2018) for MM patients with RI (RI MM cohort). For reference purposes, information on a general cohort of MM patients was generated and reported to highlight the clinical and economic burden of RI. Since the goal was to describe the burden of these patients, this study was not designed as a comparison between the 2 cohorts. Compared with the general MM cohort (n = 13,573), RI MM patients (24.9%) presented high MM-associated comorbidities. In the RI MM cohort, bortezomib-dexamethasone (45.7%), bortezomib-lenalidomide (18.6%), lenalidomide (12.3%), and bortezomib-cyclophosphamide (12.1%) were the most prevalent regimens in 1L; carfilzomib and pomalidomide were mostly received in 3L to 4L; and daratumumab in 4L. Across 1L to 4L, the RI MM cohort presented shorter median real-world progression-free survival (1L: 12.9 and 16.4 months) and overall survival (1L: 31.1 and 46.8 months) and higher all-cause healthcare resource utilization (1L incidence rate of inpatient days: 12.1 and 7.8 per person per year) than the general MM cohort. In the RI MM cohort, the mean all-cause total cost increased from 1L to 4L ($14,549-$18,667 per person per month) and was higher than that of the general MM cohort. RI MM patients presented higher clinical and economic burdens across 1L to 4L than the general MM patients in real-world clinical practice.
Topics: Humans; Multiple Myeloma; United States; Male; Female; Aged; Retrospective Studies; Medicare; Aged, 80 and over; Renal Insufficiency; Cost of Illness; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38941411
DOI: 10.1097/MD.0000000000038609 -
ELife Jun 2024SARS-CoV-2 induces delayed type-I/III interferon production, allowing it to escape the early innate immune response. The delay has been attributed to a deficiency in...
SARS-CoV-2 induces delayed type-I/III interferon production, allowing it to escape the early innate immune response. The delay has been attributed to a deficiency in the ability of cells to sense viral replication upon infection, which in turn hampers activation of the antiviral state in bystander cells. Here, we introduce a cellular automaton model to investigate the spatiotemporal spreading of viral infection as a function of virus and host-dependent parameters. The model suggests that the considerable person-to-person heterogeneity in SARS-CoV-2 infections is a consequence of high sensitivity to slight variations in biological parameters near a critical threshold. It further suggests that within-host viral proliferation can be curtailed by the presence of remarkably few cells that are primed for IFN production. Thus, the observed heterogeneity in defense readiness of cells reflects a remarkably cost-efficient strategy for protection.
Topics: SARS-CoV-2; Humans; COVID-19; Virus Replication; Immunity, Innate; Epithelial Cells; Interferons
PubMed: 38941138
DOI: 10.7554/eLife.94056 -
Archives of Dermatological Research Jun 2024Psoriasis might bring about an increased risk of liver diseases like nonalcoholic fatty liver disease and fibrosis. The impact of methotrexate on liver function is still...
Psoriasis might bring about an increased risk of liver diseases like nonalcoholic fatty liver disease and fibrosis. The impact of methotrexate on liver function is still a cause for concern, because of the studies suggesting an increased risk of liver damage and others finding no association. The focus of this study was the liver functions in psoriatic patients investigating the impact of long-term use of methotrexate on liver in psoriasis. A retrospective investigation including 140 patients with psoriasis receiving methotrexate treatment for at least 6 months and a control group consisted of 105 healthy ones was conducted. Liver function tests (AST, ALT, PLT) were assessed, and the association of baseline PASI with FIB-4 and APRI values was investigated. Additionally, FIB-4 and APRI values at baseline, 3rd, and 6th months of methotrexate treatment for psoriasis were compared. Compared with the controls, psoriatic patients exhibited significantly higher FIB-4 scores (p = 0.004). A moderate and significant correlation was observed between baseline PASI score and baseline FIB-4 score in psoriatic patients (p < 0.001, rho = 0.626). Long-term methotrexate use had no effect on APRI or FIB-4 (p = 0.104 and p = 0.475, respectively). Psoriatic patients face an elevated risk of liver fibrosis. Long-term methotrexate use does not adversely affect liver function in psoriatic patients. Noninvasive tools like APRI and FIB-4 scores can be employed to evaluate the risk of liver disease in these patients.
Topics: Humans; Methotrexate; Psoriasis; Male; Female; Middle Aged; Retrospective Studies; Adult; Liver Cirrhosis; Liver Function Tests; Liver; Dermatologic Agents; Aged; Severity of Illness Index; Non-alcoholic Fatty Liver Disease
PubMed: 38940980
DOI: 10.1007/s00403-024-03193-9 -
Clinical and Experimental Medicine Jun 2024Both atezolizumab (a PD-L1 inhibitor) plus bevacizumab (A+B) and sintilimab (a PD-1 inhibitor) plus bevacizumab (S+B) are recommended as the first-line regimen for... (Comparative Study)
Comparative Study
Both atezolizumab (a PD-L1 inhibitor) plus bevacizumab (A+B) and sintilimab (a PD-1 inhibitor) plus bevacizumab (S+B) are recommended as the first-line regimen for advanced hepatocellular carcinoma (HCC) in China. Different efficacy between the two regimens combined with transvascular intervention for unresectable HCC (uHCC) remain unknown. We retrospectively analyzed uHCC patients treated in three centers by simultaneous combination of A+B or S+B with transarterial chemoembolization (TACE) and FOLFOX-based hepatic arterial infusion chemotherapy (HAIC). Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (TRAEs) were compared. Totally 188 patients were included, with 92 and 96 administered A+B+TACE-HAIC (ABTH) and S+B+TACE-HAIC (SBTH), respectively. ORRs (62.0 vs. 70.8%, respectively; P = 0.257) and disease control rates (88.0 vs. 93.8%, P = 0.267) were similar between groups by the mRECIST criteria. ABTH showed no survival advantage over SBTH, with median PFS times of 11.7 months and 13.0 months, respectively (HR = 0.81, 95% CI, 0.52-1.26, P = 0.35) and similar OS times (HR = 1.19, 95% CI, 0.32-4.39, P = 0.8). No significant differences were observed in grade 3-4 TRAEs between groups. Either PD-L1 or PD-1 inhibitor plus bevacizumab combined with TACE-HAIC have similarly excellent therapeutic efficacy with manageable adverse events, representing promising treatment options for uHCC.
Topics: Humans; Carcinoma, Hepatocellular; Male; Bevacizumab; Middle Aged; Female; Liver Neoplasms; Retrospective Studies; Aged; Antineoplastic Combined Chemotherapy Protocols; Adult; Antibodies, Monoclonal, Humanized; Treatment Outcome; Immune Checkpoint Inhibitors; China; Chemoembolization, Therapeutic; Programmed Cell Death 1 Receptor; B7-H1 Antigen; Fluorouracil; Leucovorin
PubMed: 38940944
DOI: 10.1007/s10238-024-01415-y -
Journal of Cell Science Jun 2024Some chemotherapy drugs modulate the formation of stress granules (SGs), which are RNA-containing cytoplasmic foci contributing to stress response pathways. How SGs...
Some chemotherapy drugs modulate the formation of stress granules (SGs), which are RNA-containing cytoplasmic foci contributing to stress response pathways. How SGs mechanistically contribute to pro-survival or pro-apoptotic functions must be better defined. The chemotherapy drug lomustine promotes SG formation by activating the stress-sensing eIF2α kinase HRI (encoded by the EIF2AK1 gene). Here, we applied a DNA microarray-based transcriptome analysis to determine the genes modulated by lomustine-induced stress and suggest roles for SGs in this process. We found that the expression of the pro-apoptotic EGR1 gene was specifically regulated in cells upon lomustine treatment. The appearance of EGR1-encoding mRNA in SGs correlated with a decrease in EGR1 mRNA translation. Specifically, EGR1 mRNA was sequestered to SGs upon lomustine treatment, probably preventing its ribosome translation and consequently limiting the degree of apoptosis. Our data support the model where SGs can selectively sequester specific mRNAs in a stress-specific manner, modulate their availability for translation, and thus determine the fate of a stressed cell.
Topics: Humans; RNA, Messenger; Early Growth Response Protein 1; Lomustine; Stress Granules; Apoptosis; Antineoplastic Agents, Alkylating
PubMed: 38940347
DOI: 10.1242/jcs.261825 -
International Journal of Molecular... Aug 2024Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancer‑associated death in young people. GNE‑477 belongs to the second...
Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancer‑associated death in young people. GNE‑477 belongs to the second generation of mTOR inhibitors and possesses promising potential in the treatment of OS but dose tolerance and drug toxicity limit its development and utilization. The present study aimed to prepare a novel HO stimulus‑responsive dodecanoic acid (DA)‑phenylborate ester‑dextran (DA‑B‑DEX) polymeric micelle delivery system for GNE‑477 and evaluate its efficacy. The polymer micelles were characterized by morphology, size and critical micelle concentration. The GNE‑477 loaded DA‑B‑DEX (GNE‑477@DBD) tumor‑targeting drug delivery system was established and the release of GNE‑477 was measured. The cellular uptake of GNE‑477@DBD by three OS cell lines (MG‑63, U2OS and 143B cells) was analyzed utilizing a fluorescent tracer technique. The hydroxylated DA‑B was successfully grafted onto dextran at a grafting rate of 3%, suitable for forming amphiphilic micelles. Following exposure to HO, the DA‑B‑DEX micelles ruptured and released the drug rapidly, leading to increased uptake of GNE‑477@DBD by cells with sustained release of GNE‑477. The experiments, including MTT assay, flow cytometry, western blotting and RT‑qPCR, demonstrated that GNE‑477@DBD inhibited tumor cell viability, arrested cell cycle in G1 phase, induced apoptosis and blocked the PI3K/Akt/mTOR cascade response. , through the observation of mice tumor growth and the results of H&E staining, the GNE‑477@DBD group exhibited more positive therapeutic outcomes than the free drug group with almost no adverse effects on other organs. In conclusion, HO‑responsive DA‑B‑DEX presents a promising delivery system for hydrophobic anti‑tumor drugs for OS therapy.
Topics: Animals; Humans; Micelles; Osteosarcoma; Hydrogen Peroxide; Cell Line, Tumor; Dextrans; Mice; Lauric Acids; Apoptosis; Polymers; Xenograft Model Antitumor Assays; Bone Neoplasms; Mice, Nude; Antineoplastic Agents; Mice, Inbred BALB C; Male; TOR Serine-Threonine Kinases
PubMed: 38940336
DOI: 10.3892/ijmm.2024.5393 -
Oncology Reports Aug 2024Ferroptosis, a regulated form of cell death, is intricately linked to iron‑dependent lipid peroxidation. Recent evidence strongly supports the induction of ferroptosis... (Review)
Review
Ferroptosis, a regulated form of cell death, is intricately linked to iron‑dependent lipid peroxidation. Recent evidence strongly supports the induction of ferroptosis as a promising strategy for treating cancers resistant to conventional therapies. A key player in ferroptosis regulation is ferroptosis suppressor protein 1 (FSP1), which promotes cancer cell resistance by promoting the production of the antioxidant form of coenzyme Q10. Of note, FSP1 confers resistance to ferroptosis independently of the glutathione (GSH) and glutathione peroxidase‑4 pathway. Therefore, targeting FSP1 to weaken its inhibition of ferroptosis may be a viable strategy for treating refractory cancer. This review aims to clarify the molecular mechanisms underlying ferroptosis, the specific pathway by which FSP1 suppresses ferroptosis and the effect of FSP1 inhibitors on cancer cells.
Topics: Humans; Neoplasms; Ferroptosis; S100 Calcium-Binding Protein A4; Ubiquinone; Lipid Peroxidation; Drug Resistance, Neoplasm; Animals; Glutathione; Antineoplastic Agents; Molecular Targeted Therapy
PubMed: 38940330
DOI: 10.3892/or.2024.8764